Chronic obstructive pulmonary disease (COPD) is defined by the Global Initiative for Chronic Obstructive Lung Disease (GOLD) and the American and European Respiratory Society as a disease state characterized by airflow limitation that is not fully reversible. Cigarette smoking is the most important risk factor for the development of COPD. Although the dose-response relationship between cigarette smoking and pulmonary function is well-established, there is considerable variability in the reduction in forced expiratory volume in one second or FEVi among smokers with similar smoking exposures. Further, COPD is thought to be progressive, implying that lung function continues to decline at an accelerated rate compared to individuals who do not develop COPD. Although it is accepted that a substantial minority of smokers will develop clinical COPD most smokers are thought to have a mean decline in FEVi that is steeper than that of non-smokers. What is less known is the fact that a significant proportion of individuals at risk have no decline or even a modest increase in the FEVi over long period of observation. The current proposal is centered on the hypothesis that there are detectable differences in the serum biomarker profile between smoking subjects with a 'rapid' decline in FEVi and non-decliners. These differences are the result of different pathobiological mechanisms and provide a window for the development of therapeutic strategies to alter the accelerated decline of such patients. A major goal of this proposal is to compare the levels of serum markers on 'rapid' FEVi decliners versus non-decliners and using this tool to identify disease pathways related to these markers. The proposal is based on previous studies from our group showing differences between patients with COPD and healthy controls in the 'profile' of a panel of markers grouped into; inflammatory markers, markers related to injury and repair, and novel markers. The role of adipokines and autophagy will be explored as complementary pathways responsible for accelerated decline of lung function. We propose that the biomarker pattern can be used to develop therapeutic strategies targeting the pathways represented by the biomarkers. The work will be validated in a well characterized cohort of smokers being followed at the Lovelace Respiratory Research Institute (LRRI) in Albuquerque, New Mexico.